Clinical Gastroenterology and Hepatology 2022;20:2696–2706

CLINICAL PRACTICE UPDATES

AGA Clinical Practice Update on New Technology and
Innovation for Surveillance and Screening in Barrett’s
Esophagus: Expert Review
V. Raman Muthusamy,1 Sachin Wani,2 C. Prakash Gyawali,3 and
Srinadh Komanduri,4 for the CGIT Barrett’s Esophagus Consensus Conference
Participants
1
Vatche and Tamar Manoukian Division of Digestive Diseases, University of California, Los Angeles, Los Angeles, California;
2
Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Denver, Colorado; 3Division of
Gastroenterology, Washington University School of Medicine, St. Louis, Missouri; and 4Division of Gastroenterology and
Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

DESCRIPTION: The purpose of this best practice advice (BPA) article from the Clinical Practice Update Com-
mittee of the American Gastroenterological Association is to provide an update on advances and
innovation regarding the screening and surveillance of Barrett’s esophagus.

METHODS: The BPA statements presented here were developed from expert review of existing literature
combined with discussion and expert opinion to provide practical advice. Formal rating of the
quality of evidence or strength of BPAs was not the intent of this clinical practice update. This
expert review was commissioned and approved by the AGA Institute Clinical Practice Updates
Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high
clinical importance to the AGA membership, and underwent internal peer review by the CPUC and
external peer review through standard procedures of Clinical Gastroenterology and Hepatology.

BEST PRACTICE Screening with standard upper endoscopy may be considered in individuals with at least 3
ADVICE 1: established risk factors for Barrett’s esophagus (BE) and esophageal adenocarcinoma,
including individuals who are male, non-Hispanic white, age >50 years, have a history of
smoking, chronic gastroesophageal reflux disease, obesity, or a family history of BE or esoph-
ageal adenocarcinoma.

BEST PRACTICE Nonendoscopic cell-collection devices may be considered as an option to screen for BE.
ADVICE 2:
BEST PRACTICE Screening and surveillance endoscopic examination should be performed using high-definition
ADVICE 3: white light endoscopy and virtual chromoendoscopy, with endoscopists spending adequate time
inspecting the Barrett’s segment.

BEST PRACTICE Screening and surveillance exams should define the extent of BE using a standardized
ADVICE 4: grading system documenting the circumferential and maximal extent of the columnar lined
esophagus (Prague classification) with a clear description of landmarks and the location and
characteristics of visible lesions (nodularity, ulceration), when present.

BEST PRACTICE Advanced imaging technologies such as endomicroscopy may be used as adjunctive techniques
ADVICE 5: to identify dysplasia.

BEST PRACTICE Sampling during screening and surveillance exams should be performed using the Seattle bi-
ADVICE 6: opsy protocol (4-quadrant biopsies every 1–2 cm and target biopsies from any visible lesion).

Abbreviations used in this paper: AGA, American Gastroenterological Kingdom; US, United States; VC, virtual chromoendoscopy; WATS-3D,
Association; BE, Barrett’s esophagus; BPA, Best Practice Advice; CGIT, wide-area transepithelial sampling.
Center for GI Innovation and Technology; CI, confidence interval; CLE,
confocal laser endomicroscopy; EAC, esophageal adenocarcinoma; EET, Most current article
endoscopic eradication therapy; GERD, gastroesophageal reflux disease;
HD-WLE, high definition-white light endoscopy; HGD, high-grade © 2022 by the AGA Institute
dysplasia; LGD, low-grade dysplasia; NDBE, nondysplastic Barrett’s 1542-3565/$36.00
esophagus; OR, odds ratio; PPI, proton pump inhibitor; UK, United https://doi.org/10.1016/j.cgh.2022.06.003

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December 2022 Screening and Surveillance of Barrett’s Esophagus 2697

BEST PRACTICE Wide-area transepithelial sampling may be used as an adjunctive technique to sample the
ADVICE 7: suspected or established Barrett’s segment (in addition to the Seattle biopsy protocol).

BEST PRACTICE Patients with erosive esophagitis should be biopsied when concern of dysplasia or malignancy
ADVICE 8: exists. A repeat endoscopy should be performed after 8 weeks of twice a day proton pump
inhibitor therapy.

BEST PRACTICE Tissue systems pathology-based prediction assay may be utilized for risk stratification of pa-
ADVICE 9: tients with nondysplastic BE.

BEST PRACTICE Risk stratification models may be utilized to selectively identify individuals at risk for Barrett’s
ADVICE 10: associated neoplasia.

BEST PRACTICE Given the significant interobserver variability among pathologists, the diagnosis of BE-related
ADVICE 11: neoplasia should be confirmed by an expert pathology review.

BEST PRACTICE Patients with BE-related neoplasia should be referred to endoscopists with expertise in
ADVICE 12: advanced imaging, resection, and ablation.

BEST PRACTICE All patients with BE should be placed on at least daily proton pump inhibitor therapy.
ADVICE 13:
BEST PRACTICE Patients with nondysplastic BE should undergo surveillance endoscopy in 3 to 5 years.
ADVICE 14:
BEST PRACTICE In patients undergoing surveillance after endoscopic eradication therapy, random biopsies
ADVICE 15: should be taken of the esophagogastric junction, gastric cardia, and the distal 2 cm of the
neosquamous epithelium as well as from all visible lesions, independent of the length of the
original BE segment.

ndoscopic screening for Barrett’s esophagus (BE)
E and subsequent surveillance is supported by
current societal guidelines based on the potential for
early detection of BE, dysplasia and neoplasia, and the
option for endoscopic eradication therapy (EET), with an
overarching goal of reducing the morbidity and mortality
of esophageal adenocarcinoma (EAC).1,2 However, less
than 20% of patients diagnosed with EAC in the United
States (US) have a preceding diagnosis of BE,3 suggesting
that current screening paradigms are inadequate.
The purpose of this best practice advice article from
the Clinical Practice Update Committee of the American
Gastroenterological Association (AGA) is to provide an
update on advances and innovation regarding the
screening and surveillance of BE. The target audience is
all gastroenterologists and endoscopists, and the target
patient population is adults with known or suspected BE.
Methods
This expert review was commissioned jointly by the
AGA Institute Clinical Practice Updates Committee, the
AGA Center for GI Innovation and Technology (CGIT),
and the AGA Governing Board to provide timely guidance
on a topic of high clinical importance to the AGA mem-
bership. The AGA CGIT Consensus Conferences bring
together content experts, stakeholders (industry, regu-
latory, and payors), along with a patient advocate to
discuss current needs and gaps in innovation relevant to
the topic. This was a comprehensive didactic and dis-
cussion session created to provide a novel interactive
environment to foster the AGA CGIT mission. The topic of
this clinical practice update was thoroughly discussed by
expert faculty contributors selected by AGA CGIT, in-
dustry representatives, and the patient advocate at the
conference organized and hosted by AGA CGIT. The
content of this expert review was generated, discussed,
and voted upon by the expert faculty contributors at a
closed-door meeting during the AGA CGIT conference. All
faculty contributors provided up to date declaration of
conflicts of interest to ensure credibility of this docu-
ment, and signed off on the final manuscript, which un-
derwent internal peer review by the Clinical Practice
Updates Committee as well as external peer review
through standard procedures of Clinical Gastroenterology
and Hepatology.
Screening for Barrett’s Esophagus
Best Practice Advice 1: Screening with standard upper
endoscopy may be considered in individuals with at least 3
established risk factors for BE and EAC, including in-
dividuals who are male, non-Hispanic white, age >50
years, have a history of smoking, chronic gastroesophageal
reflux disease (GERD), obesity, or a family history of BE or
EAC.

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2698 Muthusamy et al
Current guidelines suggest endoscopic screening for
an “at-risk” population.2 The vast majority of patients
(up to 90%) with EAC have never had a diagnosis of BE.
A recent meta-analysis of 49 studies suggests that the
prevalence of BE in the GERD population is 3%, and this
increases with each additional risk factor.4 These risk
factors for BE include the presence of chronic GERD and
at least 2 of the following: age >50 years, male gender,
Caucasian race, smoking, obesity, family history of BE or
EAC.1 The highest prevalence was seen with family his-
tory along with GERD at 23.4%.4 Chronic GERD is
defined as >5 years or symptoms (heartburn or regur-
gitation) occurring frequently (weekly or greater).
However, the requirement of GERD symptoms has
significantly limited the impact of screening on detection
of EAC.
The panel discussed the limitations of chronic GERD
symptom as a mandatory prerequisite for endoscopic
screening. A recent study of prevalent EAC assessed so-
cietal guidelines in the US (n ¼ 663) and United Kingdom
(UK) (n ¼ 645) to determine the sensitivity of current
screening recommendations.1,5,6 In these cohorts, 54.9%
of the US patients and 38.9% of the UK patients would
not have been identified by current screening guidelines.
Furthermore, the reason most patients (US, 86.5%; UK,
61.4%) did not meet screening guidelines was the lack of
symptomatic GERD. Furthermore, a second study of US
veterans also identified that >50% of patients with EAC
did not have frequent GERD symptoms and would not
have met current screening guidelines.7
Multiple predictive tools have been developed iden-
tify patients at risk of BE. These tools not only use GERD
symptoms, but also multiple other clinical and de-
mographic factors implicated in BE and EAC.8 These
predictive indices have been developed for real-time risk
assessment without a prerequisite of GERD through pa-
tient assessment and questionnaires. From the available
tools, the HUNT (Nord-Trondelag Health Study), M-
BERET (Michigan BE pREdiction Tool), and Kunzmann
tools were found to be more sensitive for predicting BE
than GERD symptoms alone.8 Although further validation
of these tools is needed, they can be considered in the
clinical evaluation of patients for endoscopic screening.
The optimal number of risk factors for screening re-
mains to be well-defined and inclusion of GERD remains
fraught with several limitations. The threshold number
of risk factors is largely based on expert opinion. These
factors provided the impetus to propose a screening
approach that is not restricted to patients with GERD and
considers all defined risk factors for BE and EAC.
Therefore, screening with standard upper endoscopy
may be considered in individuals with at least 3 estab-
lished risk factors for BE and EAC, including individuals
who are male, non-Hispanic white, age >50 years, have a
history of smoking, chronic GERD, obesity, or a family
history of BE or EAC. The reduction of the valuation of
GERD in this paradigm is felt to significantly improve
detection of BE and more accurately identify the “at-risk”
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Clinical Gastroenterology and Hepatology Vol. 20, No. 12
population. Future studies should assess the impact of
this approach (benefits and harms) in screening for BE.
Best Practice Advice 2: Nonendoscopic cell-collection
devices can be considered as an option to screen for BE.
Although upper endoscopy with biopsies remains the
gold standard for the diagnosis of BE, there is a signifi-
cant need for noninvasive screening tools that are easy to
administer, patient friendly, and cost-effective for the
detection of BE. Transnasal endoscopy offers the use of
an ultrathin endoscope that can be performed in the
office setting without sedation. Although guidelines have
acknowledged this as an alternative to sedated endos-
copy, it remains costly, expert-dependent, and not
desirable to patients.2 This gap has led to the develop-
ment of multiple novel cell collection devices which offer
a nonendoscopic alternative for screening. Current non-
endoscopic cell collection devices include Cytosponge
(Medtronic GI Solutions), EsoCheck (Lucid Diagnostics),
and EsophaCap (Capnostics) (See Supplementary
Appendix). All 3 nonendoscopic devices have demon-
strated excellent tolerability, safety, and sensitivity for
the diagnosis of BE. Further data is needed to validate
patient selection and the optimal setting for adminis-
tration of these novel devices in the US.
Endoscopic Examination of Barrett’s
Esophagus
Best Practice Advice 3: Screening and surveillance
endoscopic examination should be performed using high-
definition white light endoscopy (HD-WLE) and virtual
chromoendoscopy (VC), with endoscopists spending
adequate time inspecting the Barrett’s segment.
The goal of endoscopic screening and surveillance in
BE is early detection of BE-related dysplasia and early
EAC. Consistent with recent guidelines,2,9 the panel
agrees with the routine use of HD-WLE and VC during
screening and surveillance endoscopy in patients with
BE. In an updated meta-analysis that included 504 pa-
tients, virtual chromoendoscopy with HD-WLE was
associated with a higher detection rate of HGD/EAC
compared with HD-WLE alone (14.7% vs 10.1%; relative
risk, 1.44).10 Although available data suggest comparable
rates of dysplasia detection between virtual and tradi-
tional chromoendoscopy techniques, VC is the preferred
approach as this imaging platform is available in most
endoscopes, requires no additional costs, and circum-
vents the problems associated with dye-based chro-
moendoscopy such as the need for dye spraying
equipment, additional time required, cumbersome na-
ture of the procedure, difficulty in achieving uniform
coating of the mucosal surface with the dye, and inability
to detect superficial vascular patterns.2 Incorporation of
training in virtual and traditional chromoendoscopy
during fellowship and training programs for the prac-
ticing endoscopists will be important for widespread
routine implementation in clinical practice.10 The clinical
use of VC is suggested regardless of endoscope
December 2022
Table 1. Ten-step Approach to Endoscopic Examination of Barrett’s Esophagus (BE)
Approach
1. Identify esophageal landmarks, including the location of the
diaphragmatic hiatus, gastroesophageal junction, and squa-
mocolumnar junction
2. Consider use of a distal attachment cap (especially in patients
with prior diagnosis of dysplasia)
3. Clean mucosa well using water jet channel and carefully suction
the fluid
4. Utilize insufflation and desufflation
5. Spend adequate time inspecting the Barrett’s segment and
gastric cardia in retroflexion
6. Examine the Barrett’s segment using HD-WLE
7. Examine the Barrett’s segment using chromoendoscopy
(including virtual chromoendoscopy)
8. Use the Prague classification to describe the circumferential and
maximal Barrett’s segment length
9. Use the Paris classification to describe superficial neoplasia
10. Use the Seattle protocol (in conjunction with virtual chro-
moendoscopy) with a partially deflated esophagus to sample
the Barrett’s segment
Adapted from Kolb J, Wani S. Curr Opin Gastroenterol 2020;36:351–358.60
HD-WLE, High-definition white light endoscopy.
manufacturer, but is should be clear that majority of data
supporting this is for narrow-band imaging only. There
are limited data addressing the impact of inspection time
on detection of BE-associated neoplasia in patients un-
dergoing screening and surveillance endoscopy.11-13
Conceptually, there was agreement that adequate in-
spection time would lead to more careful examination of
the BE mucosa and potentially increased detection of BE-
associated neoplasia. Future studies need to define the
optimal threshold for inspection time per cm of the BE
segment. Although the panel purposefully did not name a
time period comprising an adequate exam due to lack of
data on this issue, the European Society for Gastroin-
testinal Endoscopy and United European Gastroenter-
ology recommend a procedure time of 7 minutes for
upper endoscopy and inspection time of 1 minute/cm
of the circumferential extent of the Barrett’s mucosa.14
Although screening and surveillance upper endos-
copy may be effective in detecting dysplasia and curable
EAC, it is imperfect. Similar to post-colonoscopy colo-
rectal cancer,15 BE-associated high-grade dysplasia
(HGD) and EAC can be diagnosed before the next rec-
ommended endoscopic evaluation after an upper
endoscopy that was negative for HGD or EAC.16,17 Meta-
analyses and cohort studies suggest that a high
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Screening and Surveillance of Barrett’s Esophagus 2699
Rationale
1. Critical for future exams
2. Facilitate visualization
3. Remove any distracting mucus or debris and
minimize mucosal trauma
4. Fine adjustments to luminal insufflation can
help with detection of subtle abnormalities
5. Careful examination increases dysplasia
detection
6. Standard of care
7. Enhances mucosa pattern and surface
vasculature
8. Standardized reporting system
9. Standardized reporting system
10. Increases dysplasia detection
proportion of HGD or EAC are missed within the first
year following the index endoscopy that diagnosed
BE.18,19 To address the importance of the quality of
endoscopic examination, using an evidence-based
approach, an international working group recently
standardized terminology and definitions for post-
endoscopy esophageal adenocarcinoma and post-
endoscopy esophageal neoplasia; EAC and HGD/EAC
detected before the next recommended surveillance
endoscopy in a patient with nondysplastic BE (NDBE),
respectively.10 A conceptual 10-step approach to a high-
quality endoscopic examination in patients with BE is
highlighted in Table 1.
Best Practice Advice 4: Screening and surveillance
endoscopic examinations should define the extent of BE
using a standardized grading system documenting the
circumferential and maximal extent of the columnar lined
esophagus (Prague Classification) with a clear description
of landmarks and location and characteristics of visible
lesions (nodularity, ulceration), when present.
The panel acknowledged that the impact of use of
standardized grading criteria for BE length (Prague
classification) and visible lesions (Paris classification)
(Figure 1, A) on critical outcomes such as improved
detection of BE-associated neoplasia has not been
2700 Muthusamy et al Clinical Gastroenterology and Hepatology Vol. 20, No. 12

Figure 1. A, The Prague classification for BE. B, Illustration of the Seattle biopsy protocol for performing surveillance in pa-
tients with NDBE.59 C, Illustration of a simplified protocol for performing random surveillance biopsies in patients status post
EET. Of note, all visible lesions in the cardia and tubular esophagus should be biopsied separately.57 EGJ, Esophagogastric
junction.

assessed. The panel suggested the routine use of these
classification practices as surrogates for performance of
a high-quality endoscopy exam.
Best Practice Advice 5: Advanced imaging technologies
may be used as adjunctive imaging techniques to identify
dysplasia.
The panel were supportive of the need to have
improved imaging technologies to better identify areas
of dysplasia and early cancer. Technologies considered
for this discussion included confocal (CLE) or volu-
metric laser endomicroscopy. A meta-analysis of 14
studies of 789 patients with 4047 lesions found CLE
had a per-lesion analysis pooled sensitivity and speci-
ficity of 77% (95% confidence interval [CI], 0.73–0.81)
and 89% (95% CI, 0.87–0.90), respectively.20 A separate
meta-analysis of 5 studies involving 251 patients
assessing within-patient comparisons of narrow band
imaging and CLE found the pooled additional detection
rate of CLE for per-lesion detection of neoplasia in pa-
tients with BE was 19.3% (95% CI, 0.05–0.33), but a
comparable per-patient pooled sensitivity and speci-
ficity.21 Volumetric laser endomicroscopy, though not
currently available commercially, has introduced several
new advances with regards to imaging in BE, including
laser marking and the interpretation of imaging using
artificial intelligence.22,23 The panelists felt strongly this
was an important area where further innovation is
needed, but that the use of these techniques was not
required for a high-quality exam and the data to date
did not support its routine use. However, the panel felt
these technologies were promising and carried potential
benefits in select cases and currently might be best
utilized in expert centers.
Best Practice Advice 6: Sampling during screening and
surveillance endoscopic examinations should be performed
using the Seattle biopsy protocol (4-quadrant biopsies
every 1‒2 cm and target biopsies from any visible lesion).
The support for this structured biopsy protocol is
based on observational data suggesting that the use of
the Seattle biopsy protocol (Figure 1, B) is associated
with a higher dysplasia detection rate (relative risk,
2.75).10 The panel acknowledged that endoscopists can
meet this criterion if they prefer not to sample a visible
lesion and refer the patient for endoscopic resection.
Unfortunately, several studies have consistently demon-
strated suboptimal adherence rates to the Seattle biopsy
protocol.24-26 The odds of detecting dysplasia signifi-
cantly decreased with nonadherence to the Seattle bi-
opsy protocol (odds ratio [OR], 0.53; 95% CI,
0.35–0.82).24 A recent analysis using a national quality

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December 2022
benchmarking registry that included 58,709 endoscopies
showed that nearly 20% of endoscopies were not
adherent to the Seattle biopsy protocol, and that endo-
scopists were less adherent with increasing BE length;
with the odds of nonadherence increasing by 31% with
every 1-cm increase in length.26
Best Practice Advice 7: Wide-area transepithelial
sampling (WATS-3D) may be used as an adjunctive tech-
nique to sample the suspected or established Barrett’s
segment (in addition to the Seattle biopsy protocol).
WATS-3D is a novel method that uses an abrasive
brush to sample larger surface areas of the esophagus.
These specimens allow for analysis of large sheets of
cells while maintaining the 3-dimensional aspects of the
tissue. The tissue is analyzed by software that uses
convoluted neural networks to identify abnormal cells,
which are confirmed by an expert pathologist. A recent
systematic review and meta-analysis of 7 studies
demonstrated an incremental yield for dysplasia detec-
tion of 7.2%.27 In addition, pathologic interpretation of
these specimens has been shown to have less interob-
server variability with kappa of 0.86.28 As such, the
recent ASGE guidelines supported the use of WATS-3D in
addition to Seattle protocol in select patients (eg, inde-
terminate for dysplasia or clinically high-risk NDBE)
undergoing surveillance.2 Further prospective studies
directly comparing WATS-3D and Seattle protocol are
needed to understand if WATS-3D sampling might be as
or more effective.
Best Practice Advice 8: Patients with erosive esopha-
gitis may be biopsied when concern of dysplasia or ma-
lignancy exists, with the caveat that a repeat endoscopy
after 8 weeks of twice-daily proton pump inhibitor (PPI) is
performed.
The panel discussed the importance of preventing
delays in diagnosing dysplasia and malignancy when
concerning endoscopic findings are encountered in the
setting of esophagitis. Although the potential for over-
calling dysplasia (especially low-grade dysplasia [LGD]) in
the setting of active inflammation exists, the panel felt that
this should not preclude obtaining biopsies as expert pa-
thologists have been shown to be able to distinguish
inflammation from true LGD.29 When such samples are
obtained, documentation should be included regarding
the presence and severity of the esophagitis visualized.
Although once a day PPI may be sufficient for healing
some patients, given the potential for an incomplete
response in a subset of patients with severe esophagitis,
twice a day therapy was suggested to maximize efficacy,
especially given the limited downside to such a short
treatment course. Treatment for 8 weeks was suggested,
as this has been the typical duration of most trials of PPI
for the healing of esophagitis and has been recommended
by prior guidelines.30-32 The panel noted that a relook
endoscopy is only needed for those with Los Angeles
Grade C and D esophagitis.33 The indication for repeat
endoscopy is to document healing of esophagitis and to
assess for any features of malignancy. Furthermore,
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Screening and Surveillance of Barrett’s Esophagus 2701
follow-up esophagogastroduodenoscopy may reveal un-
derlying Barrett’s in up to 10% to 12% of patients.34-36
Risk Stratification of Barrett’s
Esophagus
Best Practice Advice 9: Tissue systems pathology-based
prediction assay may be utilized for risk stratification of
patients with NDBE.
Risk stratification among patients with NDBE has been
limited to clinical scoring systems. Recently, a tissue sys-
tems pathology assay (Tissue Cypher), commercially
available in the US, has been validated and demonstrated
to accurately risk stratify patients with NDBE (low, in-
termediate, high) for progression to HGD/EAC with a 4.7-
fold increased risk in patients stratified as high risk.37 The
assay is performed on routine biopsies from the Barrett’s
segment and quantifies 9 protein-based biomarkers (p16,
p53, AMACR, HER2, Cytokeratin 20, CD68, COX-2, HIF-
1alpha, and CD45Ro), along with nuclear morphology and
tissue architecture. It is performed on formalin-fixed,
paraffin-embedded biopsies. The result is a numeric
score from 1 to 10 that corresponds to a patient’s risk for
progression. To date, there have been 5 independent
studies including 239 progressors and 656 non-
progressors across the US and Europe. The sensitivity and
specificity for Tissue cypher for detecting progression in
patients with NDBE is 30.4% and 95%, respectively, with
the sensitivity increasing to 50% if multiple levels are
examined.38 A recent spatial-temporal analysis of pro-
gressors and nonprogressors demonstrated that a high-
risk score was associated with a rate of progression of
6.9%, similar to LGD.38 In addition, a study using Markov
modeling suggesting that Tissue Cypher-based risk strat-
ification becomes cost-effective after 5 years, with an in-
cremental cost-effectiveness ratio of $52,483/quality-
adjusted life years. Finally, a recent pooled analysis of
international studies in 472 patients with NDBE demon-
strated that a high Tissue Cypher risk score was a strong
independent predictor for progression to HGD/EAC (OR,
14.2; 95% CI, 5–39; P < .001).39 Based on these data, the
panel agreed that the Tissue Cypher assay may be of
benefit for risk stratification of patients with NDBE.
Best Practice Advice 10: Risk stratification models may
be utilized to selectively identify individuals at risk for
Barrett’s associated neoplasia.
The panel agreed on the value of using risk stratifi-
cation models to stratify surveillance intervals and in-
fluence the decision on whether to perform EET.
However, at present, the only validated clinical risk
stratification model for predicting progression to HGD/
esophageal cancer in patients with known BE is the
Progression in Barrett’s Esophagus score.40 This score
was developed from 2697 patients, of whom 154 (5.7%)
developed HGD or esophageal cancer. Factors signifi-
cantly associated with progression included baseline
confirmed LGD, male sex, smoking, and BE length. Scores
2702 Muthusamy et al Clinical Gastroenterology and Hepatology Vol. 20, No. 12

Figure 2. Suggested BE care pathway.

assigned identified patients with BE that progressed to
HGD or EAC with a c-statistic of 0.76 (95% CI, 0.72–0.80;
P < .001), with the high-risk group progressing at a rate
of 2.1% compared with 0.73% for the intermediate
group and 0.13% for the low-risk group. Of note, this
score is heavily influenced by the presence of LGD but
was found to perform better in predicting progression
than LGD alone in a separate BE cohort.41 Other non-
validated models using clinical variables have included
the presence of esophagitis, lack of PPI use, being over-
weight, increasing age, and a known duration of BE of
10 years.42-46 The panelists noted that several addi-
tional models were currently in development and noted
that models incorporating both clinical and biomarker
parameters would likely ultimately be needed to opti-
mize predictive accuracy.
Provider Expertise in Managing BE
Best Practice Advice 11: Given the significant interob-
server variability among pathologists, the diagnosis of
Barrett’s-related neoplasia should be confirmed by an
expert pathology review.
The panelists acknowledged the significant interob-
server variability in the interpretation of dysplasia
among pathologists and the importance of high-quality
expert pathology review in the diagnosis of BE-related
neoplasia.2,47 An accurate diagnosis of dysplasia is crit-
ical for clinical decision-making and risk stratification,
including the selection of endoscopic eradication therapy
vs intensive surveillance. A systematic review and meta-
analysis showed that expert pathology review resulted in
a change in the pathologic diagnosis (upgrading or
downgrading) in 55% (95% CI, 31%–77%) of all pa-
tients.47 Available data suggests LGD, as confirmed by
expert pathology review, is associated with a higher rate
of disease progression to HGD/EAC.47 P53 immunohis-
tochemistry can help confirm dysplasia and improve
consistency of reporting.48,49 This Best Practice Advice is
consistent with GI guidelines that recommend confir-
mation of dysplasia of any grade by a second pathologist
with expertise in GI pathology.9,47
Best Practice Advice 12: Patients with BE-related
neoplasia should be referred to endoscopists with exper-
tise in advanced imaging, resection, and ablation.
Physicians with expertise in Barrett’s neoplasia man-
agement have been shown to identify more visible lesions
compared with nonexperts.50 The panelists strongly felt
that physicians performing endoscopic eradication therapy
for BE-related neoplasia should either perform or work in

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December 2022 Screening and Surveillance of Barrett’s Esophagus 2703

centers that can offer both resection and ablation tech-
niques, as recommended by prior quality metrics.51 Expert
centers should ideally be defined based on adequate vol-
ume, availability of needed technology, procedural exper-
tise, and exceeding established quality metrics.
Follow-up and Surveillance of BE
Best Practice Advice 13: Patients with BE should be
placed on at least daily PPI therapy.
Epidemiologic evidence from observational studies
that have demonstrated a significant decrease in the risk
of progression to HGD and EAC in patients with BE with
PPI therapy. A systematic review and meta-analysis
showed that PPI therapy was associated with a 71%
reduction in the risk of HGD or EAC (adjusted OR, 0.29;
95% CI, 0.12–0.79).52 In 4 cohort studies that reported
the time to progression to HGD or EAC, PPI users were
also significantly less likely to progress to HGD or EAC
(adjusted hazard ratio, 0.32; 95% CI, 0.15–0.67). The
AspECT trial demonstrated that high-dose PPI was su-
perior to low-dose PPI for lengthening the time to reach
the combined end point of death from any cause, EAC, or
HGD. However, several study limitations prevent these
conclusions to be generalizable. The trial was not double-
blinded, the event rate was low, and only a small effect
size was noted. The overall benefit was skewed towards
all cause-mortality rather than cancer-related mortality,
most relevant to the BE population.53 As such, there was
insufficient information in these studies on whether
taking PPI twice daily would provide any added benefit
over once daily administration. The panel also consid-
ered the potential harms of long-term PPI therapy and
the suggested associations between PPI therapy and the
risk of several outcomes.54,55 Evidence is inadequate to
establish causal relationships between PPI and any of
these proposed associations, with the exception of
enteric infection.55 Given the unclear benefit of higher
doses of PPI on oncogenesis, the panel suggested at least
daily dosing, with higher doses considered for those
requiring them for symptom control and among patients
with BE-related neoplasia undergoing endoscopic eradi-
cation therapy.
Best Practice Advice 14: Patients with NDBE should
undergo surveillance endoscopy in 3 to 5 years.
Endoscopic surveillance in patients with known BE
remains the gold standard for dysplasia and neoplasia
detection. Current guidelines recommend endoscopic
surveillance every 3 to 5 years1 based on a low risk of
progression to HGD/EAC in patients with NDBE. Surveil-
lance intervals are shortened significantly in patients with
dysplasia but should remain 3 to 5 years for patients with
NDBE. The interval allows for gastroenterologists some
flexibility to individualize intervals for each patient. Most
recently, the American College of Gastroenterology
guidelines for 2022 recommended consideration of the
segment length when determining surveillance interval,
with longer intervals for segments <3 cm.9 Careful dis-
cussions and assessments of the value of endoscopic sur-
veillance, given other comorbidity and risks, should be a
part of the management of all patients with BE.
Best Practice Advice 15: In patients undergoing sur-
veillance after endoscopic eradication therapy (EET),
4-quadrant random biopsies should be taken of the esoph-
agogastric junction, gastric cardia, and the distal 2 cm of
the neosquamous epithelium, as well as from all visible le-
sions, independent of the length of the original BE segment.
Traditionally, 4-quadrant random post-EET sur-
veillance biopsies have been recommended in the

Best Practice Advice (BPA) Statements

Screening for Barrett’s Esophagus (BE)

BPA #1. Screening with standard upper endoscopy may be considered in individuals with established risk factors for BE and esophageal
adenocarcinoma – presence of at least 3 risk factors (individuals who are male, non-Hispanic white, age >50 years, have a history of
smoking, chronic gastrointestinal reflux disease, obesity, or a family history of BE or esophageal adenocarcinoma).
BPA #2. Nonendoscopic cell collection devices can be considered as an option to screen for BE.
Endoscopic Examination of BE
BPA #3. Screening and surveillance exams should be performed using high-definition white light endoscopy and virtual chromoendoscopy,
with endoscopists spending adequate time inspecting the Barrett’s segment.
BPA #4. Screening and surveillance exams should define the extent of BE using a standardized grading system documenting the
circumferential and maximal extent of the columnar lined esophagus (Prague classification) with a clear description of landmarks and the
location and characteristics of visible lesions (nodularity, ulceration), when present.
BPA #5. Advanced imaging technologies such as endomicroscopy may be used as adjunctive imaging techniques to identify dysplasia.
BPA #6. Sampling during screening and surveillance exams should be performed using the Seattle biopsy protocol (4-quadrant biopsies
every 1‒2 cm and target biopsies from any visible lesion).
BPA #7. Wide area transepithelial sampling may be used as an adjunctive technique to sample the suspected or established Barrett’s
segment (in addition to the Seattle biopsy protocol).
BPA #8. Patients with erosive esophagitis may be biopsied when concern of dysplasia or malignancy exists, with the caveat that a repeat
endoscopy after 8 weeks of twice a day proton pump inhibitors is performed.

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2704 Muthusamy et al Clinical Gastroenterology and Hepatology Vol. 20, No. 12

Continued

Best Practice Advice (BPA) Statements

Risk Stratification of BE
BPA #9. Tissue systems pathology-based prediction assay may be utilized for risk stratification of patients with nondysplastic BE.
BPA #10. Risk stratification models may be utilized to selectively identify individuals at risk for Barrett’s associated neoplasia.
Provider Expertise in Managing BE
BPA #11. Given the significant interobserver variability among pathologists, the diagnosis of BE-related neoplasia should be confirmed by an
expert pathology review.
BPA #12. Patients with BE-related neoplasia should be referred to endoscopists with expertise in advanced imaging, resection, and ablation.
Follow-up and Surveillance of BE
BPA #13. Patients with BE should be placed on at least daily proton pump inhibitor therapy.
BPA #14. Patients with nondysplastic BE should undergo surveillance endoscopy in 3 to 5 years.
BPA #15. In patients undergoing surveillance after endoscopic eradication therapy, 4-quadrant random biopsies should be taken of the
esophagogastric junction, gastric cardia, and the distal 2 cm of the neosquamous epithelium as well as from all visible lesions,
independent of the length of the original BE segment.

cardia, at the esophagogastric junction and every 1 References

cm in entire prior BE segment. Three studies have
reported on the anatomic location of recurrent BE
after EET.56-58 In total, they evaluated 1235 patients
achieving complete eradication of intestinal meta-
plasia and observed 233 recurrences, for an aggregate
recurrence rate of 18.9%. The majority of nonvisible
recurrence of intestinal metaplasia occurred at the
esophagogastric junction, whereas most recurrences
in the tubular esophagus were visible. Using the
aforementioned best practice statement post-EET
surveillance biopsy strategy, 98% (228/233) of all
recurrences could be identified. The panelists felt that
for a BE length of <2 cm, such an approach was still
reasonable given the potential for subsquamous/
tangential extension up to 1 cm beyond the proximal
end of the squamocolumnar junction. The panelists
also recognized the value of obtaining cardia biopsies
to assess for dysplasia (Figure 1, C).
Conclusion
Targeted BE screening and surveillance using existing
methodologies, as well as use of emerging and novel
screening technologies, have the potential to improve
early detection of dysplasia, neoplasia, and EAC within
populations at risk for BE (Figure 2).
Supplementary Material
Note: To access the supplementary material accom-
panying this article, visit the online version of Clinical
Gastroenterology and Hepatology at www.cghjournal.org,
and at https://doi.org/10.1016/j.cgh.2022.06.003.
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Correspondence
Address correspondence to: Srinadh Komanduri, MD, MS, Professor of Med-
icine and Surgery, Associate Chief, Division of Gastroenterology and Hep-
atology, Feinberg School of Medicine, Northwestern University, 676 St Clair,
14th Fl, Chicago, IL 60611. e-mail: koman1973@gmail.com.
Acknowledgments
CGIT Barrett’s Esophagus Consensus Conference contributors: Jacques
Bergman, Marcia I. Canto, Amitabh Chak, Douglas Corley, Gary W. Falk,
Rebecca Fitzgerald, Rehan Haidry, John M. Haydek, John Inadomi, Prasad G.
Iyer, Vani Konda, Elizabeth Montgomery, Krish Ragunath, Joel Rubenstein,
Jason B. Samarasena, Felice Schnoll-Sussman, Nicholas J. Shaheen, Michael
Smith, Rhonda F. Souza, Stuart J. Spechler, Arvind Trindade, Rockford G.
Yapp. Please refer to the Supplementary Materials for additional disclosures
and conflicts of interest.
Conflicts of interest
The authors disclose the following. V. Raman Muthusamy reports consultant
for Medtronic, Boston Scientific, research support from Boston Scientific;
Advisory Board: Endogastric Solutions; honoraria from Torax Medical/Ethicon;
and stock from Capsovision. Sachin Wani reports consultant for Exact Sci-
ences advisory board for Cernostics; and research support from Lucid Di-
agnostics and CDx Diagnostics. Prakash Gyawali reports consultant for
Medtronic. Srinadh Komanduri reports consultant for Medtronic, Boston Sci-
entific, Castle Biosciences, and Johnson & Johnson.
December 2022
Supplementary Appendix
Cell-collection Devices for Barrett’s Esophagus
Cytosponge. The Cytosponge is a spherical piece of
polyurethane foam within a gelatin capsule that is
attached to a suture. The capsule is swallowed by the
patient; it then dissolves upon reaching the stomach. The
foam then expands and is slowly withdrawn, sampling
the surface of the gastric cardia and esophagus. The ac-
quired cells are placed in a preservative and a paraffin
block created. Standard sections are created and stained
with hematoxylin and eosin along with trefoil factor 3, an
immunochemical biomarker for intestinal metaplasia.
The Cytosponge has been heavily tested in the United
Kingdom in the Barett’s Esophagus (BE) Screening trials
(BEST 1-3).1-3 In addition, the Cytosponge has a good
patient acceptability profile4 and shown in to have a
sensitivity of 80% and specificity of 92%2 for the
detection of BE. In a large, multicenter, pragmatic ran-
domized controlled trial (BEST 3) in the primary care
setting, Cytosponge-TFF3 demonstrated a 10-fold in-
crease in detection of BE.3 A rare case of tether detach-
ment has been described. The most common adverse
event has been throat soreness in up to 4%.3
EsophaCap. The EsophaCap or “sponge on a string”
(SOS) is similar conceptually to the Cytosponge but with
a smaller diameter, at 2.5 cm. The EsophaCap has been
studied assessing methylated biomarkers (VAV3,
ZNF682) and found to have a 100% sensitivity and
specificity for intestinal metaplasia (IM).5 This was
further studied with other methylated biomarkers and
found to have a sensitivity of 94% with specificity of
62.6%.6 However, both studies were limited in sample
size. Ultimately, a 5 methylated DNA marker panel was
validated in a multicenter study using a training (n ¼
199) and test cohort (n ¼ 89). Sensitivity of the panel
was 93% for diagnosis of BE with specificity of 90% in
the training set, whereas the sensitivity was 93% with
specificity of 93% in the test set.7 The SOS-3 validation
trial is currently underway. No significant adverse events
have been reported though data are limited.
EsoCheck. The EsoCheck device is distinct from the
string-based collection devices utilizing a balloon
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Screening and Surveillance of Barrett’s Esophagus 2706.e1
attached to a thin catheter. The balloon with ridges at the
end of the catheter is inflated and withdrawn for cell
acquisition. The balloon is inverted before withdrawal to
prevent contamination from the squamous mucosa. The
balloon is placed in a preservative and then evaluated. A
pilot study assessing the EsoCheck device using a 2-
biomarker assay (VIM and CCNA1) demonstrated a
sensitivity of 90.3% and specificity of 91.7%.8 A larger
multicenter study to further validate these findings is
underway. No significant adverse events have been re-
ported though data are limited.
Supplementary References
1. Kadri SR, Lao-Sirieix P, O’Donovan M, et al. Acceptability and
accuracy of a non-endoscopic screening test for Barrett’s
oesophagus in primary care: cohort study. BMJ 2010;
341:c4372.
2. Ross-Innes CS, Debiram-Beecham I, O’Donovan M, et al. ,
BEST2 Study Group. Evaluation of a minimally invasive cell
sampling device coupled with assessment of trefoil factor 3
expression for diagnosing Barrett’s esophagus: a multi-center
case-control study. PLoS Med 2015;12:e1001780.
3. Fitzgerald RC, di Pietro M, O’Donovan M, et al. BEST3 Trial
team. Cytosponge-trefoil factor 3 versus usual care to identify
Barrett’s oesophagus in a primary care setting: a multicentre,
pragmatic, randomised controlled trial. Lancet 2020;
396:333–344.
4. Shaheen NJ, Komanduri S, Muthusamy VR, et al. Acceptability
and adequacy of a non-endoscopic cell collection device for
diagnosis of Barrett’s esophagus: lessons learned. Dig Dis Sci
2022;67:177–186.
5. Iyer PG, Taylor WR, Johnson ML, et al. Highly discriminant
methylated DNA markers for the non-endoscopic detection
of Barrett’s esophagus. Am J Gastroenterol 2018;113:1156–
1166.
6. Wang Z, Kambhampati S, Cheng Y, et al. Methylation biomarker
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